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转录状态动态导致尿路膀癌的异质性和适应性瘤进化
Antara Biswas1, Sarthak Sahoo2, Gregory M Riedlinger3
1Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA. ab2063@cinj.rutgers.edu.
Communications biology
|December 22, 2023
概括
在泌尿器膀癌 (UBC) 中的瘤内部异质性涉及细胞在上皮和介质细胞状态之间切换. 这种可塑性推动了适应性进化,并影响了治疗反应和疾病进展.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 基因组学就是基因组学.
背景情况:
- 瘤内部异质性是治疗失败和尿道膀癌 (UBC) 存活率低下的关键因素.
- 了解这种异质性的动态性质对于开发有效的治疗策略至关重要.
研究的目的:
- 研究UBC的转录组异质性,重点关注表皮和介质细胞类状态之间的共存和过渡.
- 为了建模和描述这些转录状态的种群动态,并确定关键的监管标记.
- 探索微环境因素 (营养限制) 和治疗 (辐射) 对瘤细胞可塑性和适应性进化的影响.
主要方法:
- 对UBC队列的转录组分析.
- 细胞系中自发和可逆状态转换的建模.
- 人口动态的表征和监管标记的识别 (SMAD3,KLF4,PPARG).
- 营养限制和辐射对瘤异质性和表型的影响的评估.
主要成果:
- 在UBC中瘤内部的转录组异质性反映了具有双向转换的共存的上皮质和介质细胞类转录状态.
- 确定SMAD3,KLF4和PPARG是这些动态转录变化的关键调节者.
- 营养物质的限制和辐射最初选择了短暂的抵抗,但最终重建了异质性,推动了适应性进化.
- 低PPARG表达与UBC患者的攻击性表型相关.
结论:
- 现型可塑性和动态的,非遗传的瘤内部异质性显著调节UBC疾病的进展.
- 这种异质性在适应性治疗反应中起着至关重要的作用,影响治疗结果.
- 针对这些动态过程可能为治疗尿路膀癌提供新的途径.
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